Author:
Byrd Chelsea M.,Dai Dongcheng,Grosenbach Douglas W.,Berhanu Aklile,Jones Kevin F.,Cardwell Kara B.,Schneider Christine,Wineinger Kristin A.,Page Jessica M.,Harver Chris,Stavale Eric,Tyavanagimatt Shanthakumar,Stone Melialani A.,Bartenschlager Ralf,Scaturro Pietro,Hruby Dennis E.,Jordan Robert
Abstract
ABSTRACTDengue viruses (DENV) infect 50 to 100 million people worldwide per year, of which 500,000 develop severe life-threatening disease. This mosquito-borne illness is endemic in most tropical and subtropical countries and has spread significantly over the last decade. While there are several promising vaccine candidates in clinical trials, there are currently no approved vaccines or therapeutics available for treatment of dengue infection. Here, we describe a novel small-molecule compound, ST-148, that is a potent inhibitor of all four serotypes of DENVin vitro. ST-148 significantly reduced viremia and viral load in vital organs and tended to lower cytokine levels in the plasma in a nonlethal model of DENV infection in AG129 mice. Compound resistance mapped to the DENV capsid (C) gene, and a direct interaction of ST-148 with C protein is suggested by alterations of the intrinsic fluorescence of the protein in the presence of compound. Thus, ST-148 appears to interact with the DENV C protein and inhibits a distinct step(s) of the viral replication cycle.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
125 articles.
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